Interleukin (IL)-23 is a heterodimeric cytokine comprised of two protein subunits, designated p40 and p19 for their approximate molecular weights. The p40 protein is shared between IL-12 and IL-23, whereas the p19 protein subunit is unique to IL-23. IL-23 signals through a two-chain receptor complex consisting of the IL-12 receptor beta-1 (IL-12Rβ1) chain, which binds to p40, and a unique IL-23 receptor chain (IL23R), which confers IL-23-specific intracellular signaling.
IL-23 induces the differentiation of naïve CD4+ T cells into pathogenic IL-17-producing helper T (Th17 or ThIL-17) cells. The IL-17 secreted by this distinct helper T cell subset is an important effector cytokine during inflammation. Elevated IL-17 levels have been observed in target tissues of various autoimmune diseases and inflammatory conditions, including rheumatoid arthritis, inflammatory bowel diseases (i.e., Crohn's disease and ulcerative colitis), and psoriasis. Therefore, IL-23 has been implicated as a critical factor in inflammatory conditions and autoimmune-mediated diseases.
Several approaches to target IL-23/IL-17 signaling have been tested so far, including antibodies directed against IL-23 or the IL-23 receptor, as potential therapeutic approaches for treating inflammatory and autoimmune diseases. With respect to the use of IL-23 as a target for potential pharmacological interventions, various neutralizing antibodies directed to the p40 subunit of IL-23 have been developed for potential use in the treatment of autoimmune driven diseases. For example, the monoclonal antibody known as “ustekinumab” (Janssen-Cilag) is an antibody that targets the common p40 subunit of IL-12 and IL-23. It has been shown to be effective in the treatment of psoriasis and psoriatic arthritis. Another monoclonal antibody that targets the smaller p19 subunit of IL-23 is described in EP 2 548 577.
With regard to strategies aimed at blocking the IL-23 receptor function by IL-23 receptor-targeting antibodies, WO 2004/042009 discloses the use of a monoclonal anti-IL-23 receptor antibody or fragments thereof (Fv, Fab, Fab′ and F(ab′)2) for the treatment of an inflammatory disease associated with elevated expression of IL-17. Moreover, WO 2008/106134 discloses the generation of humanized antibodies, which recognize the IL23R chain of the human IL-23 receptor, suitable for use in the treatment of inflammatory and autoimmune disorders. These anti-IL23R antibodies include, inter alia, antibodies conjugated to cytotoxic payloads that can be used in immunotherapy to selectively target and kill cells expressing IL23R on their surface.
A promising approach for the antibody-based treatment of various cancer diseases is the redirection of immune effector cells to specifically lyse target cells using bispecific antibodies. The bispecific antibodies recognize a particular antigen on the surface of a target cell and, simultaneously, an activating surface molecule of an immune effector cell, such as a natural killer (NK) cell or a cytotoxic T (Tc) cell, to thereby kill the target cells.
The bispecific antibody concept is, for example, used in cancer therapy where bispecific antibodies are employed that bind to a cancer antigen on cancer cells and, simultaneously, to the epsilon chain of CD3 presented on, for example, cytotoxic T cells. A well-known example of such a bispecific antibody construct is “blinatumomab”, an antibody in the BiTE (bi-specific T cell engager) format, for the treatment of non-Hodgkin's lymphoma and acute lymphoblastic leukemia. Blinatumomab was developed by Micromet and simultaneously binds to the cancer antigen CD19 as well as to CD3 on the surface of cytotoxic T cells, thereby linking these two cell types together and activating the cytotoxic T cell to lyse the target cancer cell.
The hitherto most successful antibody-based approaches to treat inflammatory and/or autoimmune diseases exploit mechanisms of action that interfere with the interaction of cytokines and their respective receptors in order to prevent signaling through cytokine receptors. Examples include inhibition of TNFα (e.g., infliximab and adalimumab), inhibition of p40 (e.g., ustekinumab) or inhibition of IL6R (e.g., tocilizumab). However, these antibodies often still allow for the signaling through redundant pathways. As a consequence, a significant number of patients cannot be effectively treated. For example, up to 40% of the patients are refractory to treatment with TNFα inhibiting antibodies.
Thus, there is still a need for new and improved treatment strategies in the treatment of various diseases, such as inflammatory and/or autoimmune diseases and cancer. In particular, bispecific molecules for use in such treatments are required that are stable, easy to produce, highly specific for a given target antigen, and have a low immunogenicity.